Medical devices are commonly implanted into the body to treat various conditions. These medical devices are commonly constructed from polymers or metal, for example, a polymeric or metallic stent utilized to treat restenosis within a conduit of a body such as a blood vessel or biliary duct. The placement of metal or polymeric devices in the body can give rise to numerous complications. Some of these complications include increased risk of infection, initiation of a foreign body response resulting in inflammation and fibrous encapsulation, and/or initiation of a wound healing response resulting in hyperplasia and/or restenosis. These and other possible complications must be dealt with when introducing a metal or polymeric device into the body.
One approach to reducing the potential harmful effects is to improve the biocompatibility of the device. While there are several methods available to improve the biocompatibility of devices, one method that has met with limited success is to provide the device with the ability to deliver therapeutic and/or other biologically active agents to the vicinity of the implant. By so doing, some of the harmful effects associated with the implantation of medical devices are diminished. For example, antibiotics can be released from the device to minimize the possibility of infection, and anti-proliferative drugs can be released to inhibit hyperplasia. Another benefit is to localize the release of the therapeutic and/or biologically active agent(s) to the area where they are most needed. This avoids the spread of therapeutic and/or biologically active agent(s) to areas where they may prove toxic. It is also desired that therapeutic agents be released for long periods of time (days, weeks, or months) instead of an instantaneous release upon implant of the device.
Typically, a therapeutic agent is applied to the surface of a device via a polymer matrix. For example, in the case of a metallic device, a metal oxide is created to activate the surface. Thereafter a layer is formed on the activated metal surface that serves as a platform for a primer layer. A polymer blended with a biologically active agent or therapeutic agent that readily adheres to the primer layer may be employed. In many respects, the success of the polymer coatings depends on the nature of the contact between at least the polymer layer adjacent to the metal surface and the underlying metal surface. In particular, if the polymer cracks or peels away from the metal surface, the polymer layer having the biologically active agent will fail to perform.
Providing a device with a polymer containing a biologically active agent presents several challenges. When a polymer layer contains a biologically active agent the resulting polymer/biologically active agent composite may be prone to dilation, swelling, degradation, and/or volume changes because of interactions of the incorporated compound with aqueous environments of the body. Also, following the penetration of water into the polymer layer, dissolution of the compound and its subsequent release, may change the structure and porosity of the composite. In addition, due to penetration of water following drug dissolution, the polymer layer could be exposed to a mechanical stress due to osmotic forces. These effects may result in detachment of the polymer layer and its peeling from the metal surface.
U.S. Pat. No. 6,013,855—McPherson, describes methods for grafting hydrophilic polymers onto metal surfaces. This method included exposing the device surface to a silane coupling agent and causing the agent to be covalently bound to the hydrophilic device surface. The bonded silane layer was then exposed to a polymer such that the hydrophilic polymer became covalently bound to the silane layer. Of course, a device produced using this method will produce a primer layer that is unable to be derivatized and will remain on the device. In addition, the use of a hydrophilic polymer will expose the interface of the surface of the device and the polymer to osmotic forces that may cause separation.
The selection of the polymeric materials employed to coat the medical device is also an important consideration. There are only a small number of polymers possessing the physical characteristics that would render them useful for implantable medical devices since most devices undergo flexion and/or expansion during and upon implantation. Many polymers that demonstrate good drug release characteristics, when used alone as drug delivery vehicles, provide coatings that are too brittle to be used on devices that undergo flexion and/or expansion.
As stated above, biologically active and/or therapeutic agents are applied to medical devices to increase biocompatibility. Thus, in addition to creating a stable interface between the device and the polymer layer containing the biologically active agent, it is also desired to ensure any polymeric materials that may have an adverse affect on the body are removed. For example, after the therapeutic agent is released, several polymer layers or layers of other materials, including the primer layer will remain on the surface of the device. This can lead to undesirable complications such as restenosis and/or thrombosis. Other polymers can create an inflammatory response when implanted.
Insung S. Choi and Robert Langer, in “Surface-Initiated polymerization of 1-Lactide: coating of solid substrates with a biodegradable polymer”, Macromolecules (2001) 34, 5361-5363, discloses an in-situ polymerization of lactone polymers with stannous octoate (Sn(Oc).sub.2) as a catalyst on a solid surface such as metal modified with a hydroxyl or amine terminated silane derivative. International Publication No. WO20030068289—Rypacek et al, uses essentially the same strategy as in the Choi article to make a device having a silane layer which is modified to polymerize a composition such that a lactone polymer layer on the silane layer. This layer is bioabsorbable and provides a surface on which additional bioabsorbable polymer layers may be applied. Thus, these layers are removed after delivery of the therapeutic agent is complete. In creating the lactone polymer layer, however, a heavy metal based catalyst, such as stannous octoate, is employed and remains inside the coating. Certainly, biocompatibility is not optimized with heavy metals present in a patient's body. Moreover, the lactone polymer layer lacks adequate density. Thus, any additional polymer layer, for example, a polymer containing a biologically active agent and/or therapeutic agent, applied to the lactone polymer layer will not adhere optimally. This may cause separation of the layers causing a failure to deliver the biologically active and/or therapeutic agent.
It is desired to provide a coating for a medical device that is bioabsorbable and will provide a dense and stable platform onto which additional bioabsorbable layers may be applied.